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Current Research and Scholarly Interests

My research interest is in the use of molecular methods to understand and characterize hematological neoplasms. My current investigations focus on the use of standard karyotyping, FISH studies, flow cytometry studies, and gene sequencing for diagnostic and prognostic evaluation of hematological neoplasms.

Abstract

To provide an account of implementation of the Epic Beaker 2014 clinical pathology module at Stanford University Medical Center and highlight strengths and weaknesses of the system.Based on a formal selection process, Stanford selected Epic Beaker to replace Sunquest as the clinical laboratory information system (LIS). The rationale included integration between the LIS and already installed Epic electronic medical record (EMR), reduction in the number of systems and interfaces, and positive patient identification (PPID). The build was significantly customized and included a first of its kind Epic-to-Epic interface. This was due to the clinical laboratory serving two hospitals (pediatric and adult) with independent instances of Epic.Test turnaround times showed improvement from historical baselines, mostly because of the implementation of PPID. PPID also resulted in significant reduction in mislabeled specimens.Epic 2014 Beaker clinical pathology is a viable LIS with adequate functionality for a large academic center. Strengths include PPID and integration with the EMR. Integration provides laboratory users with ready access to the patient's relevant clinical history to assist releasing of results and gives physician and nurse providers sophisticated add-on ordering and specimen collection workflows. Areas that could use further development include specimen aliquoting, quality control reporting, and maintenance tools.

Abstract

Primary lymphoma of bone (PLB) accounts for 3% to 7% of primary neoplasms of bone and must be distinguished from more common bone tumors in the pediatric population such as osteosarcoma, Ewing sarcoma, and other small round blue cell tumors. In this study, pathology databases from 4 institutions were queried for PLB in individuals 1 to 21 years old. A total of 54 cases of PLB were identified, including 41 diffuse large B-cell lymphomas (DLBCL, 76%), 8 B-lymphoblastic lymphomas (BLL, 15%), 3 anaplastic large cell lymphomas (ALCL, 6%), and 2 low-grade follicular lymphomas (4%). The male/female ratio was 1.8:1 and median age was 16 years (range, 2-21). Patients with DLBCL were significantly older (P

Abstract

We evaluated the new Beckman Coulter DxH 800 hematology analyzer (Beckman Coulter, Miami, FL) vs the Abbott Diagnostics Cell-Dyn Sapphire (Abbott Diagnostics, Santa Clara, CA) and Beckman Coulter LH 780 hematology analyzers using 430 adult specimens. The DxH 800 provided a CBC and differential that correlated well with those of the Sapphire and LH 780, with most parameters showing correlation coefficients (r) of more than 0.97. In the instrument vs 400-cell manual differential comparison, all 3 instruments showed similar and acceptable accuracy to the reference method except for nucleated RBC (NRBC) enumeration, in which the DxH 800 and Sapphire outperformed the LH 780. We also compared clinical efficiency by determining whether flagged specimens showed abnormalities on a peripheral blood smear as defined by International Council for Standardization in Haematology criteria. The efficiency, sensitivity, and specificity of the DxH 800 were 77.0%, 87.1%, and 73.0%, respectively, compared with the Sapphire at 75.8%, 93.5%, and 68.8%, respectively, and LH 780 at 66.1%, 93.5%, and 55.3%, respectively.

Abstract

Monoclonal antibodies are standard therapeutics for several cancers including the anti-CD20 antibody rituximab for B cell non-Hodgkin lymphoma (NHL). Rituximab and other antibodies are not curative and must be combined with cytotoxic chemotherapy for clinical benefit. Here we report the eradication of human NHL solely with a monoclonal antibody therapy combining rituximab with a blocking anti-CD47 antibody. We identified increased expression of CD47 on human NHL cells and determined that higher CD47 expression independently predicted adverse clinical outcomes in multiple NHL subtypes. Blocking anti-CD47 antibodies preferentially enabled phagocytosis of NHL cells and synergized with rituximab. Treatment of human NHL-engrafted mice with anti-CD47 antibody reduced lymphoma burden and improved survival, while combination treatment with rituximab led to elimination of lymphoma and cure. These antibodies synergized through a mechanism combining Fc receptor (FcR)-dependent and FcR-independent stimulation of phagocytosis that might be applicable to many other cancers.

Abstract

We previously identified a relatively high frequency of B-cell proliferations along with simultaneous T-cell receptor gamma-chain gene (TRG) and immunoglobulin heavy chain gene (IGH) rearrangements in a series of angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified. Here, we report on a series of 74 peripheral T-cell lymphoma (PTCL) cases composed entirely of specific PTCL subtypes, including 28 cases of ALK+ anaplastic large-cell lymphoma (ALCL), 35 cases of ALK- ALCL, and 11 cases that represent other specific PTCL subtypes. We performed IGH and TRG gene rearrangement studies and in situ hybridization for Epstein-Barr virus (EBV) to determine the frequency of IGH clonality and to investigate the relationship between EBV, clonality, and associated B-cell proliferations. Using BIOMED-2 PCR assays, we detected TRG clones in 64 of 74 (86%) cases and IGH clones in 6 of 74 (8%) cases, with all IGH-positive cases exhibiting a concurrent TRG clone. Despite the detection of occasional IGH clones, there was no correlation between IGH clonality and EBV, and B-cell proliferations were not identified in any of the cases. These findings suggest that other factors contribute to IGH clonality and demonstrate that, in the absence of an associated B-cell proliferation, IGH clonality occurs infrequently (8%) in specific PTCL subtypes.

Abstract

The Wilms' tumor gene WT1 is overexpressed in most of human leukemias regardless of disease subtypes. To characterize the expression pattern of WT1 during normal and neoplastic hematopoiesis, we generated a knock-in reporter green fluorescent protein (GFP) mouse (WT1(GFP/+)) and assayed for WT1 expression in normal and leukemic hematopoietic cells. In normal hematopoietic cells, WT1 was expressed in none of the long-term (LT) hematopoietic stem cells (HSC) and very few (<1%) of the multipotent progenitor cells. In contrast, in murine leukemias induced by acute myeloid leukemia 1 (AML1)/ETO+TEL/PDGFbetaR or BCR/ABL, WT1 was expressed in 40.5 or 38.9% of immature c-kit(+)lin(-)Sca-1(+) (KLS) cells, which contained a subset, but not all, of transplantable leukemic stem cells (LSCs). WT1 expression was minimal in normal fetal liver HSCs and mobilized HSCs, both of which are stimulated for proliferation. In addition, overexpression of WT1 in HSCs did not result in proliferation or expansion of HSCs and their progeny in vivo. Thus, the mechanism by which expansion of WT1-expressing cells occurs in leukemia remains unclear. Nevertheless, our results demonstrate that the WT1(GFP/+) mouse is a powerful tool for analyzing WT1-expressing cells, and they highlight the potential of WT1, as a specific therapeutic target that is expressed in LSCs but not in normal HSCs.

Abstract

There is a growing body of evidence that supports the idea that malignant tumors are initiated and maintained by a population of tumor cells that share similar biologic properties to normal adult stem cells. This model, the cancer stem cell (CSC) hypothesis, is based on the observation that tumors, like adult tissues, arise from cells that exhibit the ability to self-renew as well as give rise to differentiated tissue cells. Although the concept of the CSC is not entirely new, advances made over the past two decades in our understanding of normal stem cell biology in conjunction with the recent application of these concepts to experimentally define CSCs have resulted in the identification of CSCs in several human malignancies.

Abstract

We report on a series of 58 cases of angioimmunoblastic T-cell lymphoma (AILT) and 59 cases of peripheral T-cell lymphoma, unspecified (PTCL-NOS). Subsets of cases from both diagnostic groups were complicated by associated B-cell proliferations, and we performed B- and T-cell clonality studies and in situ hybridization for Epstein-Barr virus (EBV) to investigate the relationship between B-cell proliferation, B-cell clonality, and EBV. Using multiplex polymerase chain reaction assays based on the BIOMED-2 collaborative study, we detected TCRgamma T-cell clones in 78 and 81% of AILT and PTCL-NOS cases, respectively, and IGH B-cell clones in 34 and 35% of AILT and PTCL-NOS cases, respectively. The majority of cases contained EBV-positive cells, including 50% of AILT and 57% of PTCL-NOS cases, and cases with B-cell proliferations were more often EBV-positive. Although a relatively high rate of B-cell clonality has been shown for AILT, our findings for PTCL-NOS differ from previous reports in that B-cell clonality was relatively frequent. Overall, a positive B-cell clone correlated, in part, with the presence of a B-cell proliferation but not with EBV. Our findings demonstrate that B-cell clonality is a common finding in AILT and PTCL-NOS, and its presence should not negate the diagnosis established by morphologic, immunophenotypic, and clinical findings.